CN111557924B - 一种奥美沙坦酯氢氯噻嗪片的制备方法及奥美沙坦酯氢氯噻嗪片 - Google Patents
一种奥美沙坦酯氢氯噻嗪片的制备方法及奥美沙坦酯氢氯噻嗪片 Download PDFInfo
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- CN111557924B CN111557924B CN202010400368.2A CN202010400368A CN111557924B CN 111557924 B CN111557924 B CN 111557924B CN 202010400368 A CN202010400368 A CN 202010400368A CN 111557924 B CN111557924 B CN 111557924B
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- olmesartan medoxomil
- hydrochlorothiazide
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Abstract
本发明公开了一种奥美沙坦酯氢氯噻嗪片的制备方法,包括如下步骤:将奥美沙坦酯和氢氯噻嗪过筛后待用;将乳糖一水合物、微晶纤维素和低取代羟丙纤维素过筛后待用;使用过筛后的乳糖一水合物冲洗过滤奥美沙坦酯和氢氯噻嗪的筛网后与过筛物混合;采用纯化水溶解羟丙纤维素后得粘合剂溶液待用;将产物混合后的共混物过筛,慢速干混得干混物料;采用粘合剂溶液进行湿法造粒得湿颗粒;将湿颗粒过筛后,干燥湿颗粒得干颗粒;将干颗粒过筛,将过筛后的颗粒混合;将硬脂酸镁过筛后,与颗粒产物润滑后压制并用欧巴代进行包衣。本发明还公开了一种奥美沙坦酯氢氯噻嗪片。本发明提供的制备方法所制备的奥美沙坦酯氢氯噻嗪片与原研药相比药物释放性能更好。
Description
技术领域
本发明涉及药物分析技术领域,具体涉及一种奥美沙坦酯氢氯噻嗪片的制备方法及奥美沙坦酯氢氯噻嗪片。
背景技术
奥美沙坦酯是一种选择性非肽类血管紧张素II受体拮抗剂,在抗高血压市场上引起了广泛的关注。该药通过选择性阻断血管紧张素II与血管平滑肌AT1受体的结合而阻断血管紧张素II的收缩血管作用,不良反应较小,病人耐受性好,在轻中度高血压治疗中疗效良好。
氢氯噻嗪是一种适用于轻、中度高血压、尤其适宜于老年人收缩期高血压及心力衰竭伴高血压的治疗的噻嗪类利尿剂,其化学名称为6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺酰胺-1,1-二氧化物。
奥美沙坦酯是一种BCS II类化合物,其在整个生理pH范围内的水溶解度均较差,而氢氯噻嗪是一种BSC Iv类化合物,但可以认为其具有高溶解度(基于作为最高剂量的25mg和溶解度研究)和低渗透性III类化合物。
因此如何进行奥美沙坦酯氢氯噻嗪片的有效制备,使得药物的溶出和溶解程度更高,也是提高药物治疗的有效方法。
发明内容
为了克服现有技术的上述缺陷,本发明的目的之一在于提供一种奥美沙坦酯氢氯噻嗪片的制备方法。
本发明的目的之二在于提供由所述溶出度测定方法测定的奥美沙坦酯氢氯噻嗪片。
为了实现本发明的目的之一,所采用的技术方案是:
一种奥美沙坦酯氢氯噻嗪片的制备方法,包括如下步骤:
步骤一:
通过18#筛将奥美沙坦酯过筛,并通过30#筛将氢氯噻嗪过筛后收集在单独的第一、第二HDPE容器中待用;
步骤二:
通过40#筛将乳糖一水合物、微晶纤维素和低取代羟丙纤维素分别过筛后各自收集在第三、第四、第五HDPE容器中待用;
步骤三:使用所述步骤二当中过筛后的乳糖一水合物分别冲洗步骤一中的奥美沙坦酯和氢氯噻嗪的筛分残留后与筛分后的奥美沙坦酯和氢氯噻嗪混合;
步骤四:通过24#筛将所述步骤一至三当中的产物混合后的共混物过筛,并收集在第六HDPE容器中,后转移至混合研磨机中慢速干混得干混物料;
步骤五:采用纯化水溶解羟丙纤维素后得粘合剂溶液待用;
步骤六:采用所述步骤五的粘合剂溶液对所述步骤四所得的干混物料进行湿法造粒得湿颗粒;
步骤七:将步骤六当中的湿颗粒通过10#筛进行过筛后,使用入口温度为30–70℃的流化床干燥机干燥所述过筛后的湿颗粒,直至LOD不超过4%w/w得干颗粒;
步骤八:
通过30#目筛将所述步骤七制得的干颗粒过筛后收集进行研磨、整粒,将所述研磨整粒后的颗粒混合1-20分钟;
步骤九:
将硬脂酸镁采用60#筛过筛后,与所述步骤八的产物混合1-10分钟后压制得素片;
步骤十:用欧巴代包衣系统对压制后的素片进行包衣得奥美沙坦酯氢氯噻嗪片。
在本发明的一个优选实施例中,所述奥美沙坦酯氢氯噻嗪片的规格为40mg/25mg或20mg/12.5mg或40mg/12.5mg。
在本发明的一个优选实施例中,所述奥美沙坦酯氢氯噻嗪片中,奥美沙坦酯粒度(D90)低于10μm且氢氯噻嗪粒度(D90)为15-50μm。
在本发明的一个优选实施例中,所述的乳糖一水合物为pharmatose 200m,所述乳糖一水合物的用量为5%-70%。
在本发明的一个优选实施例中,所述的低取代羟丙纤维素为L-HPC-LH-21,所述低取代羟丙纤维素的用量为1%-10%。
在本发明的一个优选实施例中,所述的粘合剂当中,羟丙纤维素的含量为1-10%,优选为2.31%,所述硬脂酸镁的浓度为0.25%-5%,优选为0.5%-1.5%。
在本发明的一个优选实施例中,所述的湿法造粒当中,粘合剂溶液浓度为10-60%,优选为43%,造粒时间为1-20min,优选为4min30sec;
所述混合为在双锥混合机进行混合,所述双锥混合机的转速为1-30rpm;
所述压制为使用15.1×7.10mm和8.5mm的椭圆形冲头压制。
在本发明的一个优选实施例中,所述欧巴代包衣系统当中包括羟丙甲纤维素、二氧化钛、滑石粉、氧化铁红、氧化铁黄以及纯化水,使得对压制片包衣后达到最高0.5%-6%的增重;所述HDPE容器为内衬双LDPE袋的HDPE容器。
为了实现发明的目的之二,所采用的技术方案是:
一种奥美沙坦酯氢氯噻嗪片,其中,所述奥美沙坦酯氢氯噻嗪片由所述溶出度测定方法测定。
本发明的有益效果在于:
本发明提供了一种溶出度更高的奥美沙坦酯氢氯噻嗪片的制备方法,所制备的奥美沙坦酯氢氯噻嗪片与原研药相比药物释放性能更好。
附图说明
图1为原研片的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL pH 6.8磷酸盐缓冲液中的溶出曲线图。
图2为本发明制备的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL pH 6.8磷酸盐缓冲液中的溶出曲线图。
图3为原研片的奥美沙坦酯氢氯噻嗪片20mg/12.5mg使用USP装置II以50rpm的转速运行时在900mL pH 6.8磷酸盐缓冲液中的溶出曲线图。
图4为本发明制备的奥美沙坦酯氢氯噻嗪片20mg/12.5mg使用USP装置II以50rpm的转速运行时在900mL pH 6.8磷酸盐缓冲液中的溶出曲线图。
图5为原研片的奥美沙坦酯氢氯噻嗪片40mg/12.5mg使用USP装置II以50rpm的转速运行时在900mL pH 6.8磷酸盐缓冲液中的溶出曲线图。
图6为本发明制备的奥美沙坦酯氢氯噻嗪片40mg/12.5mg使用USP装置II以50rpm的转速运行时在900mL pH 6.8磷酸盐缓冲液中的溶出曲线图。
图7为原研片的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL水中的溶出曲线图。
图8为本发明制备的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL水中的溶出曲线图。
图9为原研片的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL 0.1N HCl中的溶出曲线图。
图10为本发明制备的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL 0.1N HCl中的溶出曲线图。
图11为原研片的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL pH 4.5醋酸盐缓冲液中的溶出曲线图。
图12为本发明制备的奥美沙坦酯氢氯噻嗪片40mg/25mg使用USP装置II以50rpm的转速运行时在900mL pH 4.5醋酸盐缓冲液中的溶出曲线图。
具体实施方式
奥美沙坦酯
在由血管紧张素转化酶(ACE,激肽酶II)催化的反应中,血管紧张素I形成血管紧张素II。血管紧张素II是肾素-血管紧张素系统的主要升压剂,其作用包括血管收缩、刺激醛固酮合成和释放、心脏刺激和肾脏对钠的重吸收。奥美沙坦通过选择性地阻断血管紧张素II与血管平滑肌中AT1受体的结合来阻断血管紧张素II的血管收缩作用。因此,其作用独立于血管紧张素II的合成途径。也在许多组织中检出了AT2受体,但尚不知该受体是否与心血管稳态有关。奥美沙坦对AT1受体的亲和力是对AT2受体的亲和力的12,500多倍。用ACE抑制剂(可抑制血管紧张素I生物合成血管紧张素II)对肾素-血管紧张素系统进行的阻断是许多高血压治疗药物的机理。ACE抑制剂还可抑制缓激肽的降解,这也是ACE催化的反应。因为奥美沙坦酯不会抑制ACE(激肽酶II),所以不影响对缓激肽的反应。尚不清楚此差异是否具有临床意义。血管紧张素II受体的阻断可抑制血管紧张素II对肾素分泌的负调节反馈,但升高的血浆肾素活性和循环血管紧张素II水平并不能克服奥美沙坦对血压的影响。
氢氯噻嗪
氢氯噻嗪是一种噻嗪类利尿剂。噻嗪类可影响肾小管的电解质重吸收机理,这可直接增加钠和氯的排泄量(大约相等的量)。间接的作用是,氢氯噻嗪的利尿作用可降低血浆体积,从而导致血浆肾素活性升高、醛固酮分泌升高、尿钾流失升高以及血清钾降低。肾素-醛固酮链接是由血管紧张素II介导的,所以血管紧张素II受体拮抗剂的共同给药往往会逆转与这些利尿剂有关的钾流失。尚不完全清楚噻嗪类的降压作用机理。
而奥美沙坦酯的药物释放度和溶解度在不同介质下释放情况不同,为了将复配的奥美沙坦酯氢氯噻嗪片更好的进行利用,建立奥美沙坦酯氢氯噻嗪片体外溶出度的测定方法至关重要。
乳糖一水合物:
乳糖在片剂和胶囊剂中广泛用作填充剂或稀释剂,并在一定程度上用于冻干产品和婴儿配方食品。可商购具有不同物理性质(如粒度分布和流动特性)的各种乳糖级别。这样可以为特定应用选择最合适的物料;例如,为胶囊剂选择的粒度范围往往取决于所用胶囊封装机的类型。通常,通过湿法造粒法制备片剂或在加工过程中进行研磨时,使用精细级乳糖,因为细粒度可以与其他处方成分更好地混合,并且可以更有效地利用粘合剂。
微晶纤维素:
微晶纤维素广泛用于药品,主要在口服片剂和胶囊剂处方中用作粘合剂/稀释剂,用于湿法造粒和直接压制工艺。除了用作粘合剂/稀释剂外,微晶纤维素还具有一些润滑剂和崩解剂性质,从而使其可用于压片。
虽然文献中已报告微晶纤维素可能会以物理方式结合或吸附原料药,但处方溶出度研究中无明显的此类物理交互作用。
从文献中知道,微晶纤维素在压制过程中经历塑性变形,因为其是纤维材料,而且在本质上具有延展性。基于湿法造粒工艺中的应用和使用时的压制性质,选择微晶纤维素作为稀释剂或填充剂。
低取代羟丙纤维素(L-HPC LH-21):
LHPC是纤维素的低取代羟丙基醚。其为非离子性,对活性成分的反应性低,在水和乙醇中不溶,但在水中溶胀(因水分子保持在分布在纤维素骨架上的羟丙基周围)。L-HPC用作片剂、颗粒剂或其他药物固体剂型的双功能性辅料(粘合剂-崩解剂),具体取决于其粒度和取代基含量。
含有L-HPC的片剂会崩解成非常细的单粒微粒,从而使药物快速溶出。L-HPC Lh-21是一种中等纤维材料,其平均粒度为45,通常用于干混和湿法造粒工艺。
羟丙纤维素(HPC-L):HPC是纤维素的一种醚,其中,用环氧丙烷使重复葡萄糖单元中的一些羟基经过羟丙基化,从而形成OCH2CH(OH)CH3基团。每个葡萄糖单元中取代羟基的平均数称为取代度(DS)。完全取代时,DS为3。由于所添加的羟丙基基团含有羟基,因此在HPC制备过程中也可以将其醚化。发生此情况时,每个葡萄糖环中的羟丙基基团摩尔数(取代摩尔数(MS))可能高于3。
由于纤维素具有非常高的结晶性,因此HPC的MS必须大概在4左右,才能在水中达到良好的溶解度。HPC具有疏水基团和亲水基团的组合,因此在45℃时具有较低的临界溶液温度(LCST)。在低于LCST的温度下,HPC在水中易溶;在超过LCST的温度下,HPC不溶。在低水平下,可用作片剂粘合剂。
常规粉末型HPC主要以溶液形式使用。作为用于湿法造粒的粘合剂,低粘度级别的HPC可赋予良好的规格和美观但不会影响崩解性,从而在口服固体剂型片剂中达到极佳的性能平衡。因此选择了低粘度(6-10mPa.s)的羟丙纤维素(HPC-L)。
硬脂酸镁:
硬脂酸盐是来源于非转基因植物脂肪酸的金属硬脂酸盐(镁、锌、钙和铝)一族。这些疏水性产品以细小、不可浸渍的白色粉末形式提供,具有一致的粒度。其是最常用的片剂润滑剂,本发明当中优先选择了植物级硬脂酸镁(Ligamed MF-2V)。
薄膜包衣系统是一种预混薄膜包衣材料,含有以下成分:
1.羟丙甲纤维素:
其有几种级别,这些级别的粘度和取代程度有所不同。在口服产品中,羟丙甲纤维素主要用作片剂粘合剂,用于薄膜包衣,以及在缓释片处方中用作基质。根据粘度级别,将2%-20%w/w的粘度的羟丙甲纤维素用于薄膜包衣片的成膜溶液。较低粘度级别用于水性薄膜包衣溶液,而较高粘度级别与有机溶剂一起使用。
2.二氧化钛:
二氧化钛在糖果、化妆品和食品、塑料工业以及局部和口服药物制剂中用途广泛,主要用作颜料。
由于其折射率高,二氧化钛具有光散射性质,从而将其用作白色颜料和遮光剂。
3.滑石粉:
滑石粉是由水合硅酸镁组成的矿物,化学式为H2Mg3(SiO3)4或Mg3Si4O10(OH)2。松散形式是广泛使用的物质,称为滑石粉。其为叶状至纤维团,极罕见的形式为晶体形式。其具有完美的底面解理。滑石粉在口服固体剂型中广泛用作润滑剂和助流剂,滑石粉在包衣组成中主要作为抗粘剂使用。
4.氧化铁红:主要作为着色剂使用。
5.氧化铁黄:主要作为着色剂使用。
纯化水:
其在粘合剂溶液制备和包衣溶液制备中用作溶剂。
实施例如下表1所示:
表1
本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)和(20mg/12.5mg)的成分用量如下表2所示。
表2
*奥美沙坦酯的量根据含量测定值和水分变化。
**氢氯噻嗪的量根据含量测定值和LOD变化。
***需基于奥美沙坦酯的含量测定值和水分以及氢氯噻嗪的含量测定值和LOD调整乳糖一水合物的用量。
#在干燥过程中蒸发。
一、以0.05M pH 6.8磷酸盐缓冲液为溶出介质的溶出度对比:
将本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)与原研片溶出度数据见表3和图1、图2。
表3
由表2和图1、图2可知,在0.05M pH 6.8磷酸盐缓冲液的溶出介质条件下,本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)当中的奥美沙坦酯与现有技术的奥美沙坦酯相比,溶出度更好,且氢氯噻嗪的溶出效果也非常稳定。
将本发明所制备的奥美沙坦酯氢氯噻嗪片(20mg/12.5mg)与原研片溶出度数据表4和图3、图4。
表4
由表4和图3、图4可知,在0.05M pH 6.8磷酸盐缓冲液的溶出介质条件下,本发明所制备的奥美沙坦酯氢氯噻嗪片(20mg/12.5mg)当中的奥美沙坦酯与现有技术的奥美沙坦酯相比,溶出度更好,且氢氯噻嗪的溶出效果也非常稳定。
将本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/12.5mg)与原研片溶出度数据见表5和图5、图6。
表5
由表5和图5、图6可知,在0.05M pH 6.8磷酸盐缓冲液的溶出介质条件下,本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/12.5mg)当中的奥美沙坦酯与现有技术的奥美沙坦酯相比,溶出度更好,且氢氯噻嗪的溶出效果也非常稳定。
二、以水作为溶出介质下的溶出度对比:
将本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)与原研片溶出度数据见表6和图7、图8。
表6
由表6和图7、图8可知,在水作为溶出介质条件下,本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)当中的奥美沙坦酯与现有技术的奥美沙坦酯相比,溶出度更好,且氢氯噻嗪的溶出效果也非常稳定。
三、以900mL 0.1N HCl作为溶出介质下的溶出度对比:
将本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)与原研片溶出度数据见表7和图9、图10。
表7
由表7和图9、图10可知,在900mL 0.1N HCl作为溶出介质条件下,本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)当中的奥美沙坦酯与现有技术的奥美沙坦酯相比,溶出度更好,且氢氯噻嗪的溶出效果也非常稳定。
四、以900mL pH 4.5醋酸盐缓冲液作为溶出介质下的溶出度对比:
将本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)与原研片溶出度数据见表8和图11、图12。
表8
由表8和图11、图12可知,在900mL pH 4.5醋酸盐缓冲液作为溶出介质条件下,本发明所制备的奥美沙坦酯氢氯噻嗪片(40mg/25mg)当中的奥美沙坦酯与现有技术的奥美沙坦酯相比,溶出度更好,且氢氯噻嗪的溶出效果也非常稳定。
接着对较高粒度的活性成分进行了比较,采用了如下的粒度数据:
奥美沙坦酯粒度(D90)低于10μm且氢氯噻嗪粒度(D90)为15-50μm。
将上述粒度的材料与较高粒度的材料相比的结果见下表9:
表9(在500ml pH 1.2(0.1H HCl)的介质条件下)
由上表9可知,奥美沙坦酯粒度(D90)低于10μm且氢氯噻嗪粒度(D90)为15-50μm在500ml pH 1.2(0.1H HCl)的介质条件下是更好的。
不同的造粒条件下,奥美沙坦酯和氢氯噻嗪(40mg/25mg)的溶出度结果见下表10;
表10
由上表10可知,在造粒液浓度为43%,造粒时间为4min30sec的条件下,在500mlpH 1.2(0.1H HCl)的介质条件下是更好的。
使用不同的粘合剂羟丙纤维素添加量条件下,奥美沙坦酯和氢氯噻嗪(40mg/25mg)的溶出度结果见下表11:
表11。
由上表11可知,在羟丙纤维素添加量:2.31%的条件下,在500ml pH 1.2(0.1HHCl)的介质条件下是更好的。
不同润滑剂水平下,奥美沙坦酯和氢氯噻嗪(40mg/25mg)的溶出度结果见下表12。
表12
由表12可知,在0.50-1.50的浓度下,奥美沙坦酯和氢氯噻嗪(40mg/25mg)的溶出度均有比较好的表现,且以1.0的浓度为佳。
Claims (6)
1.一种奥美沙坦酯氢氯噻嗪片的制备方法,其特征在于,包括如下步骤:
步骤一:
通过18#筛将奥美沙坦酯过筛,并通过30#筛将氢氯噻嗪过筛后收集在单独的第一、第二HDPE容器中待用;
步骤二:
通过40#筛将乳糖一水合物、微晶纤维素和低取代羟丙纤维素分别过筛后各自收集在第三、第四、第五HDPE容器中待用;
步骤三:使用所述步骤二当中过筛后的乳糖一水合物分别冲洗步骤一中的奥美沙坦酯和氢氯噻嗪的筛分残留后与筛分后的奥美沙坦酯和氢氯噻嗪混合;
步骤四:通过24#筛将所述步骤一至三当中的产物混合后的共混物过筛,并收集在第六HDPE容器中,后转移至混合研磨机中慢速干混得干混物料;
步骤五:采用纯化水溶解羟丙纤维素后得粘合剂溶液待用;
步骤六:采用所述步骤五的粘合剂溶液对所述步骤四所得的干混物料进行湿法造粒得湿颗粒;
步骤七:将步骤六当中的湿颗粒通过10#筛进行过筛后,使用入口温度为30 – 70℃的流化床干燥机干燥所述过筛后的湿颗粒,直至LOD不超过4% w/w得干颗粒;
步骤八:
通过30#目筛将所述步骤七制得的干颗粒过筛后收集进行研磨、整粒,将所述研磨整粒后的颗粒混合1-20分钟;
步骤九:
将硬脂酸镁采用60#筛过筛后,与所述步骤八的产物混合1-20分钟后压制得素片;
步骤 十:用欧巴代包衣系统对压制后的素片进行包衣得奥美沙坦酯氢氯噻嗪片;
所述奥美沙坦酯氢氯噻嗪片中,奥美沙坦酯粒度D90低于10 μm且氢氯噻嗪粒度D90为15 -50 μm;
所述的乳糖一水合物为pharmatose 200m,所述乳糖一水合物的用量为5%-70%;
所述低取代羟丙纤维素的用量为1%-20%;
所述微晶纤维素的用量为5%-70%;
所述的粘合剂溶液当中,羟丙纤维素的含量为1-10%,所述硬脂酸镁的浓度为0.25%-5%;
所述的湿法造粒当中,粘合剂溶液浓度为10-60%,造粒时间为1-20min;
所述欧巴代包衣系统当中包括羟丙甲纤维素、二氧化钛、滑石粉、氧化铁红、氧化铁黄以及纯化水,使得对压制片包衣后达到最高0.5%-6%的增重。
2.如权利要求1所述的一种奥美沙坦酯氢氯噻嗪片的制备方法,其特征在于,所述奥美沙坦酯氢氯噻嗪片的规格为40mg/25mg 或20mg/12.5mg或40mg/12.5mg。
3.如权利要求1所述的一种奥美沙坦酯氢氯噻嗪片的制备方法,其特征在于,所述的微晶纤维素为Avicel® PH 101。
4.如权利要求1所述的一种奥美沙坦酯氢氯噻嗪片的制备方法,其特征在于,所述的低取代羟丙纤维素为L-HPC-LH-21,所述低取代羟丙纤维素的用量为1%-10%。
5.如权利要求1所述的一种奥美沙坦酯氢氯噻嗪片的制备方法,其特征在于,
所述共混为在双锥混合机进行共混;
所述压制为使用15.1 × 7.10 mm和8.5mm的椭圆形冲头压制。
6.如权利要求1所述的一种奥美沙坦酯氢氯噻嗪片的制备方法,其特征在于,所述HDPE容器为内衬双LDPE袋的HDPE容器。
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CN102119930A (zh) * | 2010-07-13 | 2011-07-13 | 福建天泉药业股份有限公司 | 一种奥美沙坦酯片及制备方法 |
US20110256221A1 (en) * | 2008-12-30 | 2011-10-20 | Farhad Farshi | Pharmaceutical formulations of olmesartan |
CN102836161A (zh) * | 2012-04-09 | 2012-12-26 | 珠海亿邦制药股份有限公司 | 一种以奥美沙坦酯与苯磺酸氨氯地平及氢氯噻嗪混合组成的药物的复方制剂 |
CN108125914A (zh) * | 2016-12-01 | 2018-06-08 | 北京万生药业有限责任公司 | 一种奥美沙坦酯氢氯噻嗪复方制剂 |
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US20110256221A1 (en) * | 2008-12-30 | 2011-10-20 | Farhad Farshi | Pharmaceutical formulations of olmesartan |
CN102119930A (zh) * | 2010-07-13 | 2011-07-13 | 福建天泉药业股份有限公司 | 一种奥美沙坦酯片及制备方法 |
CN102836161A (zh) * | 2012-04-09 | 2012-12-26 | 珠海亿邦制药股份有限公司 | 一种以奥美沙坦酯与苯磺酸氨氯地平及氢氯噻嗪混合组成的药物的复方制剂 |
CN108125914A (zh) * | 2016-12-01 | 2018-06-08 | 北京万生药业有限责任公司 | 一种奥美沙坦酯氢氯噻嗪复方制剂 |
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